Agricultural workers including rural veterans are routinely exposed to aerosolized environmental dust and are at heightened risk for chronic lung disease due to exaggerated airway inflammatory responses. Our work has focused on defining inflammatory aspects of organic dust exposures and investigated strategies of inflammation inhibition to prevent lung injury. Our current proposal aims to identify mechanisms for controlling lung recovery after damaging airway exposures as both the initiation and resolution of inflammation are critical in whether disease develops. Our pilot data suggests the epidermal growth factor receptor (EGFR) agonist amphiregulin (AREG) promotes lung repair pathways following exposures to dust extracts (DE) derived from swine concentrated animal feeding operations. Importantly, our preclinical studies suggest the polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) obtained by diet may enhance the production of AREG following DE exposure and protect against DE-induced lung inflammation and injury. Thus, our overall objective is to determine the contribution of AREG to lung repair pathways following inflammatory organic inhalant exposures. By identifying regulatory patterns of normative lung repair processes, we aim to identify intervention strategies to improve lung repair processes in agricultural workers suffering from lung disease. We hypothesize that AREG- mediated signaling following organic dust exposures promotes lung repair activities, and dysregulation of these normative lung repair processes leads to lung disease in agriculture workers. We have developed three specific aims to test this hypothesis: Aim 1: Identify the function of AREG in mediating lung repair following organic dust exposures. We propose to (a) determine the time course of AREG production following DE exposures in vitro and in vivo, (b) determine the effect of AREG inhibition on DE-induced lung inflammatory and recovery processes in vivo using our well-established mouse model, (c) identify the effect of exogenous AREG treatment on DE-induced lung inflammatory and recovery processes in vivo,(d) delineate the functional effects of AREG on human bronchial epithelial cell (HBEC) wound healing processes during DE exposures using a novel lung scaffolding model. Aim 2: Define the mechanisms regulating AREG activities in the lung following organic dust exposures. We will (a) determine the lung cellular contributions of AREG following DE exposures in vivo, (b) identify the EGFR-mediated pro-repair signaling events downstream of AREG binding in DE-exposed HBEC, (c) identify the contributions of tumor necrosis factor-a converting enzyme (TACE) on lung recovery following repetitive DE exposures in vivo and (d) determine the role of TACE on HBEC wound healing processes in the context of DE exposures. Aim 3: Identify how PUFA regulate AREG-mediated lung repair following organic dust exposures. We propose to (a) identify the signaling mechanism by which PUFA modulate AREG production in DE-treated HBEC, (b) assess the role of high omega 3 (n-3) and 6 (n-6) diets on lung repair processes following DE exposure in vivo, (c) investigate the role of n-3 and n-6 PUFA on HBEC lung repair processes ex vivo and (d) utilize an established cohort of veterans with agriculture exposures and chronic lung disease to assess PUFA intake, AREG production, and parameters of lung disease. ! !